Project Summary/Abstract: This proposal details a five-year research and training plan with a scientific focus on a newly discovered population of T cells, termed `T peripheral helper' (Tph) cells, that is markedly expanded in the joints of patients with rheumatoid arthritis. The candidate led a study that identified and defined this CD4+ T cell subset (Rao et al, Nature, 2017). Tph cells display a unique capacity to infiltrate inflamed tissues and drive B cell responses within the tissue. The long-term objective of the proposed study is to understand signals that regulate the development and function of Tph cells in the hope of discovering pathways that can be manipulated therapeutically to treat autoimmune diseases. The specific aims proposed here utilize three complementary approaches to evaluate the regulation of Tph cells. Aim 1 will determine conditions that drive human T cell differentiation towards a Tph cell phenotype. Aim 2 interrogates the control of Tph cell function by 3 compelling transcriptional regulators that are overexpressed in Tph cells. Aim 3 evaluates the developmental relationship of Tph cells in RA synovial tissue samples with other synovial T cell populations, including T follicular helper cells. Using a combination of mechanistic studies, patient-derived samples, and cutting-edge technologies, this study will provide the candidate with new training in several key aspects of human translational immunology. The candidate's immediate career development goals are to gain experience with bioinformatic and biostatistical analyses, interpretation of transcriptomic data, genomic manipulation of primary human cells, and scientific communication. A specific career development plan is described by both the candidate and the mentors: Dr. Michael Brenner MD, an expert in lymphocyte biology and synovial inflammation, and Dr. Soumya Raychaudhuri MD PhD, an expert in bioinformatics, capitalizing on the powerful resources at Brigham and Women's Hospital and Harvard Medical School. The candidate's long-term career goal is to attain a tenure- track faculty position pursuing research that integrates high-dimensional analyses of patient samples with detailed mechanistic analyses to develop new methods to diagnose and treat rheumatic diseases.